immunosuppressants Flashcards
rheumatoid arthritis pathophysiology
Inflammatory change and proliferation of synovium
leading to dissolution of cartilage and bone
can lead to erosion of the joint
more expression of pro inflammatory cytokines (IL1,IL6, TNFalpha)
antibodies produced by B cells: Rheumatoid factor, Anti-CCP antibodies
clinical criteria for Ra
• Morning stiffness more than 1 hour • Arthritis of more than 3 joints • Arthritis of hand joints • Symmetrical arthritis • Rheumatoid nodules
non-clinical criteria for RA
• Serum rheumatoid factor/Anti-CCP antibodies • X-ray changes
treatment goals
Symptomatic relief Prevention of joint destruction
treatment strategies for Ra
• Early use of disease-modifying drugs • Aim to achieve good disease control • Use of adequate dosages • Use of combinations of drugs • Avoidance of long-term corticosteroids drug induced remission
Treatment goals in SLE & vasculitis
- Symptomatic relief e.g arthralgia, Raynaud’s phenomenon
- Reduction in mortality
- Prevention of organ damage
- Reduction in long term morbidity caused by disease and by drugs
corticosteroids mechanism
Upregulate anti-inflammatory and downregulate pro-inflammatory genes
(• Prevent interleukin IL-1 and IL-6 production by macrophages • Inhibit all stages of T-cell activation)
corticosteroid examples
Non-biologics • Sulphasalazine gut and joint • Hydroxychloroquine lupus, immuno modulatory effect Biologics • Anti-TNF agents • Rituximab • IL-6 inhibitors, JAK inhibitors
Azathioprine indication
• SLE & vasculitis -as maintenance therapy
steroid sparing drug
atopic dermatitis, bulbous skin disease
Azathioprine mechanism
• metabolized by TPMT
• TPMT gene highly polymorphic Low/absent TPMT levels = Risk of
myelosupression • Therefore test TPMT activity before prescribing
Inhibits synthesis of purines needed for DNA and RNA replication
#Azathioprine (All immunosuppressants)
• Bone marrow suppression – Monitor FBC • Increased risk of malignancy • Increased risk of infection • Hepatitis – Monitor LFT
Other immunosuppressants -caution
Calcineurin inhibitor examples
Ciclosporin & tacrolimus
Calcineurin inhibitor indication
transplantation, atopic dermatitis, psoriasis
Calcineurin inhibitor
renal toxicity, gum hypertrophy
check BP, eGRF regularly
^ Calcineurin inhibitor
CYP 450 drugs inducers and inhibitors
Calcineurin inhibitor mechanism
Active against helper T-cells, preventing production of IL-2 via calcineurin inhibition
reduce helper T-cell activity
Mycophenolate mofetil indication
transplantation
induction, maintenance of lupus nephritis
maintenance of vasculitis
Mycophenolate mofetil mechanism of action
- impairs B- and T-cell proliferation
* spares other rapidly dividing cells (due to guanosine salvage pathways in other cells)
Mycophenolate mofetil
• Most common include nausea, vomiting, diarrhea
• Most serious is myelosuppression
caution with vaccinations
Cyclophosphamide indication
– Lymphoma, leukaemia, solid cancers
– Lupus nephritis
– Wegener’s granulomatosis (ANCA-vasculitis)
caution with vaccinations
Cyclophosphamide action
Alkylating agent -cross links DNA so that it cannot replicate
– suppresses T and B cell activity
prodrug, converted in liver by CYP450, excreted by kidney.
metabolites:toxic to the bladder epithelium and can lead to hemorrhagic cystitis
• This can be prevented through the use of aggressive hydration and/or Mesna)
cyclophosphamide
• Significant toxicity – increased risk of bladder cancer, – Infertility – monitor FBC – Adjust dose in renal impairment max 30g in a lifetime
methotrexate indication
RA,
malignancy, psoriasis, Crohn’s disease
Unlicensed roles: Inflammatory
myopathies,vasculitis, steroid-sparing agent in asthma
methotrexate mechanism of action
• Mechanism of action in non-malignant disease e.g. RA, psoriasis is NOT CLEAR
• Mechanism is not via anti-folate action
Inhibition of accumulation of adenosine
– the inhibition of T cell activation
– suppression of intercellular adhesion molecule expression by T cells
Malignant:
inhibits the synthesis of DNA, RNA and proteins
hence cytotoxic
methotrexate pharmacokinetics
• WEEKLY NOT DAILY DOSING ,bioavailability increases S/C,
50% protein bound-
NSAIDs drug-drug interaction,
renal excretion
methotrexate
• mucositis • marrow suppression both respond to folic acid supplementation • Highly teratogenic, abortifacient Rare: • hepatitis, cirrhosis, • pneumonitis • infection risk
sulfasalazine mechanism
disease modification • T-cell – inhibition of proliferation – possible T-cell apoptosis – inhibition of IL-2 production • Neutrophil – reduced chemotaxis and degranulation poorly absorbed- active in intestine effective in IBD
Release 5-aminosalicylic acid (5-ASA) - immunosuppressive
sulfasalazine
• Mainly due to sulfapyridine moiety – myelosuppression – hepatitis – Rash • Milder side effects – nausea – abdo pain/vomiting safe in pregnancy , hypersensitivity
anti TNF alpha mechanism
reduce Inflammation
reduce Cytokine cascade
reduced Recruitment of leukocytes to joint
elaboration of adhesion molecules production of chemokines
reduced Angiogenesis
reduced Joint destruction, Bone resorption and erosion, Cartilage breakdown
TB and TNF
TNFα is essential for development + maintenance of granulomata
Screen for latent TB before anti-TNF treatment
TNFα is released by macrophages in
response to M TB infection
rituximab mechanism
causes B cell apoptosis
Very effective in RA.
corticosteroid
Immunosuppression, adrenal insufficiency,
^ corticosteroids
Affected by CYP inducers,
bleeding risk increased with NSAIDs,
insulin
